A nerve cell serves as a 'single' for studies

Nerve cells derived from human stem cells often serve as the
basis for research into brain diseases. However, these cells
differ considerably in their quality and produce varying results.
Scientists around the world are therefore looking for simple cell
models that lead to consistent results when an experiment is
repeated. Research teams from the University of Bonn, the Vrije
Universiteit Amsterdam and the Max Planck Institute for
Experimental Medicine in Göttingen describe a model derived from
stem cells that consists of only one human nerve cell. It was
obtained from pluripotent stem cells through a fast forward
programming method and provides highly standardized conditions
for investigating nerve cell functions. The two studies have now
been published in the international journal Cell
Reports.

Using cell reprogramming, so-called induced pluripotent stem
cells (iPS cells) can be generated from a blood or skin sample.
The body cells are reset into an embryonic stage and are then
able to differentiate further into a huge variety of cell types
again such as heart muscle or brain cells. The expectations of
these all-rounders are accordingly high. "Nerve cells produced
from iPS cells are nowadays the most attractive tool for
research into brain diseases and pharmaceutical research," said
Prof. Dr. Oliver Brüstle from the Institute of Reconstructive
Neurobiology at the University Hospital Bonn (UKB).

Such human nerve cells derived from iPS cells can vary
considerably. Depending on the cell culture method and
production route chosen, they react very differently in
experiments. "However, we are looking for a cell model that is
able to produce the same results when an experiment is
repeated," explains Dr. Michael Peitz from Brüstle's team.
After all, the results of the studies should be statistically
verified.

For this reason, the UKB scientists, together with the Max
Planck Institute (MPI) for Experimental Medicine in Göttingen
and the Vrije Universiteit Amsterdam, developed and tested a
cell culture model consisting of a single nerve cell obtained
from human iPS cells via a highly standardized cell programming
method. This "single" sits on glial cells, which are natural
neighbors of nerve cells and crucial for their maintenance and
function.

The nerve cell is talking to itself

The special feature: The "single" brain cells talks to itself
because its main nerve fiber (axon) ends up connecting to
processes of the same nerve cell. "In principle, it's a single
neurons with a short-circuit," explains Dr. Kristina Rehbach,
one of the lead authors of the two studies at the Institute of
Reconstructive Neurobiology at the UKB. This allows the
scientists to eavesdrop on the "single" nerve cell chatting
with itself.

The circular signal transmission between the axon and the
respective neuron takes place via synapses. These are
interfaces at which electrical signals cause the release of
messenger substances, which again lead to electrical impulses
on the receiver side. Here the signals can be amplified or
reduced. The scientists at the MPI in Göttingen and the Vrije
Universiteit Amsterdam tested how this single-cell model
behaves in stimulation experiments. They used both neurons
responsible for excitation in the brain as well as inhibitory
nerve cells. "We were able to demonstrate that this model,
which consists of only a single nerve cell, yields highly
reproducible data in the functional tests and thus represents a
very good basis for high-throughput experiments," says Prof.
Dr. Matthijs Verhage from the Vrije Universiteit Amsterdam.

Various applications

The research team sees many possible applications for the
"single" nerve cell model. It can be used to study disease
mechanisms. "For example, if a protein at a synapse is altered
by a gene mutation, the consequences for signal transmission
can be observed directly in this model," said Prof. Brüstle.
Another advantage is that iPS cells reprogrammed from the skin
or blood of patients can be used to generate neurons with
disease- and patient-specific features. The cell model could of
particular interest for pharmaceutical research because it is
standardized, scalable and applicable to a wide variety of
brain diseases.

"The excellent cooperation of the various research teams in
this project shows that the combination of stem cell technology
and functional synapse biology opens up entirely new
perspectives," says Prof. Dr. Jeong Seop Rhee from the MPI for
Experimental Medicine in Göttingen. All three research teams
work together in the European joint project COSYN.

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